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Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

2016; Cell Press; Volume: 29; Issue: 4 Linguagem: Inglês

10.1016/j.ccell.2016.03.012

1878-3686

Wei Wei, Young Shik Shin, Min Xue, Tomoo Matsutani, Kenta Masui, Huijun Yang, Shiro Ikegami, Yuchao Gu, Ken Herrmann, Dazy Johnson, Xiangming Ding, Kiwook Hwang, Jung-Woo Kim, Jian Zhou, Yapeng Su, Xinmin Li, Bruno Bonetti, Rajesh Chopra, C. David James, Webster K. Cavenee, Timothy F. Cloughesy, Paul S. Mischel, James R. Heath, Beatrice Gini,

Microtubule and mitosis dynamics

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.